The overarching objective of this Project is to identify genetic variants and environmental factors that act, whether interactively or Independently (main effects), to influence the expression of a wide range of psychosocial, behavioral and biological characteristics [CVD and Type 2 Diabetes (T2D) endophenotypes] that increase the risk of developing CVD and T2D among healthy persons as well as increase the risk of adverse clinical events in persons in whom CVD is already manifest. To achieve this objective we shall use three samples - PPG-1 (N=165), Caregiver (170 caregivers of a relative with Alzheimer's Disease, 170 controls) and PPG-2 (644 from 400 families); with a total N of 1000+/- - in which we have extensive data re a broad range of T2D and CVD endophenotypes to identify promising genetic variants (using both candidate genes and GWAS-derived SNPs) that are associated with these predisease endophenotypes. A major thrust of our work on this Project will be to increase our confidence in the reality of these gene endophenotype associations by replicating them, both within the three samples used by Project 1 and in the large healthy and clinical CAD samples being studied in Projects 2 and 3. A third aim will be to work closely with Projects 2 and 3 to complete the translational process, by showing that the genetic variants found associated in Project 1 with T2D and CVD endophenotypes are also associated in those Projects' samples with both the prevalence and incidence of CVD and T2D and clinical course.